Two distinct pathogenic human retroviruses displaying tropism for CD4+ T cells have now been identified. The type 1 human T-cell leukemia virus (HTLV-1) transforms CD4+ T cells and has the etiological agent of Acquired Immune Deficiency Syndrome (AIDS) also infects CD4+ cells, but retrovirus, in addition to CD4+ T cells, has been shown to infect myeloid cells of monocytic lineage. Transcription and replication of both HTLV-1 and HIV-1 in peripheral blood lymphocytes is triggered by antigenic or mitogenic stimulation of T cells suggesting that activation of DNA binding transcription factors regulate the production of these two viruses. Mitogen or antigen induced proliferation of T cells is associated with the expression of the cellular proto-oncogene c-myb which is also expressed at high levels in CD4+ T cells and myeloid cells which are the targets of HIV- 1 infection. In a recent study, we have shown that Myb binds and transactivates HIV-1 LTR sequences suggesting that this protein could play an important role in the transcriptional regulation of these viruses. In this application, we propose to carry out a detailed investigation of the role played by this nuclear proto-oncogene in the transcription and replication of HIV-1 and HTLV-1. The aims of the proposal are: 1. To define the role of Myb-binding sequences in the transcriptional regulation of HIV-1 LTR. 2. To define the role of Myb-LTR interactions in HIV replication. 3. To examine whether co-operative interactions exist between c-myb and other transcriptional factors that bind to HIV-1 LTR. 4. To define the role of Myb-binding sequences in the transcriptional regulation of HTLV-1 LTR. To achieve these goals, we will mutagenize the Myb-binding sites in HIV-1 LTR either alone or in combination with other nuclear-factor binding sites (such as NF-kB and NFAT-1) and study their effect on HIV-1 transcription and replication. Similarly, we will carry out mutagenesis of Myb-binding sites in HTLV-1 LTR and study the effect of these mutations on HTLV-1 LTR mediated transcription.